Perspective on the Current Pharmacotherapeutic Strategies for Management of Functional Neuroendocrine Tumor Syndromes

Abstract

Introduction:

In the past the inability to control the hormone-excess-state was the main determinant of survival in patients with Functional Neuroendocrine Neoplasm syndromes (F-NENs). This could prove especially difficult because the pharmacological armamentarium available until relatively recently was limited. In the last few years there have been a marked increase in the therapeutic strategies available which have opened new pharmacotherapeutic approaches, but have also generated some controversies, uncertainties and confusion.

Areas covered:

In this perspective, the authors briefly review the different F-NENs that are established as well as those proposed; the rationale for approaching their treatment and why both an approach to controlling their hormone-excess-state and their malignant nature is required in most cases; the current recommended initial pharmacotheraputic approach to controlling the hormone-excess-state of the different F-NENs; the secondary approaches to controlling the hormone-excess-state if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN per se. Also discussed are the controversies the new treatments have generated particularly related to the timing of the diagnosis of the F-NEN, as well as the sequences of secondary treatments, and the exact role of PRRT.

Expert Opinion:

Unfortunately, except for patients with insulinomas(>90-95%), gastrinomas(<20-40%), a minority with the other F-panNEN syndromes and 0-<1% with Carcinoid syndrome is curative surgery possible allowing control of the hormone-excess-state and the malignant nature of most NENs(except insulinomas-being-95%). Except for insulinomas, gastrinomas and ACTHomas, long-acting somatostatin analogues are the initial pharmacological treatments for hormone-excess-state. For insulinomas prior to surgery/malignant insulinomas, diazoxide/frequent,small feedings are the initial treatments; for gastrinomas, oral PPIs need to be started as soon as possible and for ACTHomas Steroidogenesis inhibitors are generally initially used. There are now a number of secondary pharmacotherapeutic treatments for the different syndromes, including older drugs which are effective in some patients as well as newer therapies. These include telotristast for Carcinoid syndrome[primarily for the diarrhea, but also helps flushing in some patients]; mTor inhibitors(everolimus); pasireotide; and a number of newer agents effective in patients with ectopic Cushing syndrome. Particularly promising, is recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.

Short-ABSTRACT

Introduction:

In the past controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes(F-NENs). This was difficult because the pharmacological-armamentarium available was limited. More recently therapeutic strategies available have increased, opening new pharmacotherapeutic-approaches,but also generated controversies/uncertainties.

Areas covered:

In this perspective, the authors briefly review current established/proposed F-NENs; the rationale for treatments; the current recommended initial-pharmacotheraputic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN per se. Also discussed are controversies/uncertainties related to the new treatments.

Expert Opinion:

Unfortunately,except for patients with insulinomas(>90-95%), gastrinomas(<20-40%),a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas,gastrinomas and ACTHomas,long-acting somatostatin-analogues are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignant,diazoxide is initial drug-treatment; for gastrinomas,oral PPIs; and for ACTHomas Steroidogenesis inhibitors. There are now a number of secondary pharmacotherapeutic treatments for the different F-NEN-syndromes.These include telotristast(Carcinoid-syndrome; mTor- inhibitors(everolimus); pasireotide; and some newer agents in ectopic Cushing-syndrome. Particularly promising,is recent results with PRRT for the hormone-excess-state,independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.

1. Introduction

Pancreatic Neuroendocrine Neoplasms(panNENs) and carcinoid tumors(GI-NEN, Lung-NEN, etc.)are now classified as Neuroendocrine Neoplasms(NENs), because of their numerous shared features and arise from the diffuse neuroendocrine system throughout the respiratory and gastrointestinal tract, and in other tissues[1–4]. These cells can synthesis and often secrete numerous peptides, amines, as well as neuron-specific enolase, synaptophysin, and chromogranins[1–3].

Both panNENs and carcinoid tumors in different locations may be associated with a specific functional syndrome(F-NEN)due to ectopic secretion of a bio-active peptide, in addition to secreting numerous substances which do not cause distinct functional syndromes(chromogranin, neuron-specific enolase, synaptophysin, ghrelin, etc.)[1,2,4]. Sixteen different F-panNEN syndromes have been described(See Table 1 for most prominent)including 9 syndromes which are well-described group(>50-100 cases): Insulinomas, gastrinomas(Zollinger-Ellison syndrome), Glucagonomas, VIPomas(Pancreatic Cholera, Verner-Morrison syndrome), somatostatinomas,(SSomas), GRFomas, ACTHomas, PTHrPomas, and panNENs associated with carcinoid syndrome[3–5]. Seven additional F-panNEN syndromes which include only small number of patients(<5 cases), but are generally accepted as causing a distinct functional syndrome have been described which include: panNENs secreting renin(Reninoma), luteinizing hormone, enteroglucagon, cholecystokinin(CCKoma),erythropoietin, GLP-1, and insulin-like growth factor II[3–6]. A number of other panNENs have been reported in some studies to cause a functional syndrome, including NENs secreting neurotensin, pancreatic polypeptide, ghrelin, calcitonin and other peptides, but which are not established to be associated with a specific syndrome, and thus generally are included in the NF-panNEN group[3–5]. Other NENs(Carcinoids)can also cause a specific functional syndrome, the carcinoid syndrome, which occurs characteristically when liver metastases are present(>95% of cases)and rarely with NENs which can drain into venous systems circumventing the liver(Bronchial, pancreatic, ovary, testis)[3,4,7–9].

Table 1:

F-NEN syndromes, hormone-excess state symptoms and primary/secondary treatments

F-NET syndrome	Main Symptoms/sign	Initial Medical treatment	Secondary medical treatments[other treatments]
Carcinoid syndrome	Diarrhea(58-!00%)	Long-acting SS analogues	Telotristat, PRRT, interferon, serotonin receptor antagonist
	Flushing(45-96), Wheezing(3-18%) Carcinoid Heart disease(14-41%)	Long-acting SS analogues	PPRT, Interferon, telotristat [Valve replacement] [radio-embolization, hepatic embolization/chemo-embolization}
Insulinoma	Hypoglycemic-Sx= Neuropsychiatric(92%)-confusion(51%),altered consciousness((38%) Adrenergic Sx-Sweating(43%),Tremulousness (23%)	Frequent small feedings, Diazoxide	Long-acting SS analogues, PRRT(malignant insulinomas),everolimus, pasireotide, beta-blockers, calcium blockers, phenytoin [surgery as soon as possible] [radio-embolization, hepatic embolization/chemo-embolization}
Gastrinoma (Zollinger-Ellison syndrome)[ZES]	Pain (26-98%), GERD(0-56%), peptic ulcer disease(71-93%) Diarrhea(17-73%) GI bleeding(8-75%)	PPIs	Histamine H2-receptor antagonists>> Long-acting SS analogues [surgery if possible]
Glucagonoma	Diabetes (22-90%) Diarrhea (14-18%) Dermatitis(NME) (54-90%)	Long-acting SS analogues, amino acid infusion	Parenteral nutrition, ?PRRT [surgery if possible] [radio-embolization, hepatic embolization/chemo-embolization}
VIPoma(Verner-Morrison syndrome, Pancreatic cholera)	Large volume diarrhea (89-100%) Hypokalemia(67-100%)) Dehydration(44-100%) Flushing(14-33%)	Long-acting SS analogues Fluid/electrolyte replacement	PRRT, Glucocorticoids,loperamide, clonidine, sunitinib, Pasireotide,indomethacin,metoclopramide, lithium,phenothiazines [surgery if possible] [radio-embolization,hepatic embolization/chemo-embolization}
Pancreatic ACTHoma	Cushing’s syndrome (100%)	Steroidogenesis inhibitors	Mitotane,Dopamine agonists, long-acting somatostatin analogues, pasireotide, PRRT [surgery of primary tumor if possible; adrenalectomy]
Less frequent panNEN syndromes
SSoma	Diabetes, Diarrhea, Gallbladder disease, weight loss	Long-acting SS analogues	?PRRT,[surgery if possible]
GRFoma	Acromegaly		Pasireotide, ?PRRT [surgery if possible]
PTHrPoma	Hyperparathyroidism		Cinacalcet,bisphosphonates/rehydration, ?PRRT,[surgery if possible]

Abbreviations: ACTHoma (pancreatic)-Adrenocorticotropin releasing hormone ectopically in pancreas; F-NEN syndrome-distinct functional neuroendocrine neoplasm syndrome due to distinct release of biologically active hormone/amine; GI-gastrointestinal ; GERD-gastroesophageal reflux disease ; GRFoma-Growth hormone-releasing factor secreting NEN; H_2-receptor antagonists-Histamine H2-receptor antagonists; NME-necrolytic migratory erythema; PPI-proton pump inhibitors; PTHrPoma-panNEN secreting parathromone-related peptide causing hyperparathyroidism; SS-somatostatin analogues (Long-acting forms-Octreotide-LAR, Lanreotide-Autogel); SSoma-somatostatinoma causing the somatostatinoma syndrome; sx-symptoms; VIPoma-vasoactive intestinal polypeptide secreting NEN

The presence of a F-NEN markedly changes the clinical management because these patients now have two separate clinical aspects that need to be dealt with. Clinicians not only must deal with the potential malignant nature of the NENs, but also management of the hormone-excess-state[4,7,10]. Whereas successful surgical resection would immediately solve both problems, unfortunately this is not possible in almost all patients with Carcinoid syndrome and in 30-80% of patients with non-insulinoma panNENs(i.e. insulinomas are only malignant in <5-10% of cases)[10,11]. History has repeatedly shown us that in many cases the immediate and long-term control of the hormone-excess state is essential in these patients[4,10,12,13]. This is especially the case in patients with gastrinomas; VIPomas; some with insulinomas, especially those with malignant tumors; patients with pancreatic ACTHomas(which are malignant in >90%), and many with Carcinoid syndrome. For example, prior to the availability of histamine H₂-receptor antagonists to control the acid secretion in patients with ZES, the main cause of death was a complication of severe peptic ulcer disease such as perforation, bleeding, penetration and sepsis[12–15].

2. Approach to diagnosis and starting pharmacological management

An important aspect that is uncommonly discussed, but is quite important, is if the diagnosis is suspected, when should the diagnostic studies be performed in relation to when the pharmacological control of the hormone-excess state is begun. To make the diagnosis of F-NENs, an unphysiological secretion of the hormone must be demonstrated[3–5]. This is usually performed by demonstrating an inappropriately elevated plasma/serum level of the hormone in the presence of a prominent biologic response(i.e. hypergastrinemia in the presence of acid hypersecretion, hyperinsulinemia during marked hypoglycemia, etc.)[3,4,16]. This can be an issue with F-NENs treated with somatostatin analogues, because they can decrease the ectopic hormone release, affecting the plasma hormone levels and control the hormone-excess state, thus complicating the diagnosis[17]. The same could occur with the use of PRRT or other medical treatments(diazoxide in insulinomas, telotristat in Carcinoid syndrome, etc.)which can decrease the hormone secretion rate. The opposite occurs in in nonZES with PPI treatment causing hypergastrinemia, as will be discussed further below, because PPI treatment leads to physiological hypergastrinemia secondary to inducing hypo/achlorhydria[16,18–20]. makes it very difficult to diagnose ZES definitively in most patients while taking these drugs[16,19–21] . A similar situation exists in referral centers because patients are invariably taking such medications when they are first referred if the diagnosis is strongly suspected, and this can complicate the subsequent diagnosis. The issue then becomes whether and when to stop the medications to firmly establish the diagnosis.

In most patients with possible carcinoid syndrome, if initially seen and the patient is untreated(not taking telotristat, long-acting somatostatin analogues)and the symptoms are not severe, urinary or plasma 5-HIAA levels can be determined prior to treatment to establish the diagnosis[7,10,22]. Most patients with insulinomas(>90%)are identified early in the disease course, without advanced disease, and can have the hypoglycemic symptoms controlled with frequent small feedings without additional medications prior to surgery, which allows time to establish the diagnosis by assessing during a 72 hr fast, the plasma insulin, proinsulin, glucose, and C-peptide levels[3,4,23]. Similarly, in most patients with glucagonomas, GRFomas, SSomas, and the other infrequent panNEN syndromes, emergent immediate treatment is not required, and time can be taken to establish the diagnosis prior to start of pharmacologic therapy.

In contrast, immediate treatment of the hormone-excess state in needed in almost all patients with ZES, who frequently have acid hypersecretion rates up to 5–10-times normal and advanced peptic disease, as well as patients with VIPomas with high volume diarrhea, hypokalemia and dehydration[4,5,24–27]. This allows little time for diagnostic studies prior to antisecretory treatment. However, if possible, in ZES patients , fasting serum gastrin levels, and gastric fluid pH at the time of a pretreatment UGI endoscopy, as well as the prominence of gastric folds during the endoscopy(which are increased in >90% of ZES patients)should be assessed[5,18,19,21,28]. Similarly, in patients with high volume diarrhea with possible VIPoma, a plasma VIP and gastrin levels, as well as 24-hour stool volume and fecal electrolytes assessed when first seen, if possible[4,5,27,29].

In patients already on antisecretory drug treatments the establishment of the diagnosis of ZES is the most difficult and controversial[16,21,30]. This occurs because stopping the PPI can be difficult and not without potential risk[20,21]. This occurs because these drugs have a long duration of action(up to one week), they induce hypo-/achlorhydria in nonZES patients and thus cause physiological hypergastrinemia to levels seen in ZES hence mimic ZES, and there are numerous reports of severe peptic complications is patients with ZES when the PPI is stopped[16,20,21]. To establish the diagnosis classically requires an elevated serum gastrin level in the presence of a gastric pH of ≤2, and thus patients may have to be off the PPI for up to a week[16,18,21]. The diagnosis of ZES is further complicated by the fact that the use of a secretin provocative test to make the diagnosis in equivocal cases is not valid while taking PPIs and recent studies report many serum gastrin assays are not reliable[16,21,30–33]. Because of the difficulty of making the diagnosis of ZES, it is generally recommended that these patients be referred to a specialty center versed in this disease, without stopping the antisecretory drugs to confirm the diagnosis[16,21].

3. Approach initial pharmacological management(Table 1)

As is evident from Table 1, for the initial treatment of Carcinoid syndrome and all of the F-panNEN syndromes except ZES, insulinoma, and ACTHomas, the recommended pharmacological treatment is with somatostatin analogues of which two are approved(Lanreotide, octreotide)[4,7–10,17,22,23,27,34]. Long-acting preparations of each of these are now generally used(Octreotide-LAR, Lanreotide autogel) allowing monthly dosing, with the most frequent dosing being octreotide 20-30mg/mo or Lanreotide Autogel 60-120mg/mo[7–10,17]. These doses provide at least partial symptom control(diarrhea, wheezing) in most patients with Carcinoid syndrome(60-95%)and complete control in 40-70% [7–9,17]. In panNEN syndromes such as glucagonoma, GRFoma and VIPoma they provide at least partial symptomatic control in >70%[17,22,23,27,35,36]. Unfortunately, an escape phenomenon or tachyphylaxis may develop with time[7,10,17,22,23,27,36–38]and additional treatments may be required as discussed in the following section.

In patients with ZES, to control the acid hypersecretion, PPIs are the drugs of choice(Table 1), with all approved PPIs(omeprazole,lansoprazole,esomeprazole, pantoprazole, rabeprazole,dexpansoprazole)shown to be effective[4,5,26]. Because at the beginning of therapy many patients have peptic disease, frequently with ulcers[15,28], an initial dose equivalent to omeprazole 60 mg/day is recommended in patients with uncomplicated ZES(not associated with Multiple Endocrine Neoplasia-type1(MEN1), moderate/severe GERD, previous gastric acid - reducing surgery-Bilroth 2)[26,39–42]. Once the acid hypersecretion is controlled and mucosal healing occurs the dosage can be reduced in >60% to the equivalent dosage of omeprazole 20 QD[40,41]. In patients with complicated ZES an initial dose equivalent to omeprazole 40-60 BID is recommenced, which with time after symptom control and mucosal healing, can be reduced to 20 BID in most patients[40,41]. Many physicians initially start with lower omeprazole-equivalent doses, which do not control the hypersecretion in all patients[41–43], however, if careful, regular follow-up is used combined with adequate endoscopic assessment prior to treatment, this is a reasonable alternate approach. In the very rare patients who cannot take PPIs, histamine H₂ receptor antagonists can be used, but frequent(4-6 hourly), high-dosing(equivalent to ranitidine 300-600 mg/4-6 hr)is required, as well as gastric acid testing to assess efficacy, which is rarely available[44–47]. Long-term treatment with PPIs has proven safe, and efficacious, without the development of tachyplaxis[41,48]. It is important to remember that these patients, if not surgically cure(<40%), require life-long PPI treatment, and during times when oral drugs cannot be taken(GI illnesses, surgeries,etc.), parenteral PPIs should be used[4,5,11,49–51]. Of the increasing number of potential side effects being described within long term PPI treatment in nonZES patients[19], only the development of low levels of vitamin B12 have been regularly reported in some ZES patients with long-term PPI treatment[52].

In patients with insulinomas, many can have their symptoms initially, adequately controlled with frequent, small feedings and if not, then by the addition of diazoxide, which inhibits insulin release by inhibiting ATP-sensitive potassium channels on the insulinoma cells[4,23,53,54]. This is effective in 47-50%, however, its use can be associated with prominent side-effects which can limit its continued use[53–56]. Side-effects include edema due to fluid/electrolyte retention(thus, generally diazoxide is used with a diuretic), as well as hirsutism, thrombocytopenia, and renal failure[23,53–57]. In most patients this treatment is short-term, allowing time to perform tumor localization studies(see paragraph below for more detail). This is the case because >90% of insulinoma patients can be surgically cured[4,22,58].

In patients with ACTHomas, especially those with pancreatic tumors(40–90% malignant), many have severe Cushing’s syndrome[5,59–66], which can be difficult to control long-term medically, and thus may require a bilaterally adrenalectomy, especially if widespread metastases to the liver,etc. prevent complete surgical resection of the primary/metastatic tumor. Pharmacological treatment to attempt to restore eucortisolemia as quickly as possible, is generally initially with steroidogenesis inhibitors(ketoconazole, metyrapone)which can have frequent side-effects, although there are some reported cases that respond to long-acting-somatostatin analogues which are generally well-tolerated[23,59,60]. PRRT may prove particularly helpful in malignant/refractory cases of Cushings syndrome[60,67–69].

4. Approach to secondary pharmacological management(Table 1)

For most patients with F-NEN syndromes, except those with ZES(gastrinomas)treated with PPIs, with time, the primary pharmacologic treatment becomes less effective[10,17,23,27,38]. Numerous approaches have been reported to be effective in different patients. For F-NEN patients treated with long-acting somatostatin analogues as their primary treatment(carcinoid syndrome, some F-panNENs, Table 1), it is reported that increasing the monthly dosage, shortening the time interval of dosing to 3 weeks or shorter and supplementing with subcutaneous shorter acting octreotide, all have value in overcoming the decreasing drug effectiveness[7,8,10,17,23]. Another approach is to switch to another drug or treatment[7,8,10,17,23]. These are summarized in Table 1 and only a few specific cases will be further discussed here.

In the case of Carcinoid syndrome , the recent approval of telotristat, a tryptophan hydroxylase 1 inhibitor that works peripherally to inhibit the synthesis of serotonin, which is important particularly in the pathogenesis of the diarrhea in these patients, and in some patients also contributes to the flushing[7–10,70]. In 40-44% of patients with Carcinoid syndrome treated with telotristat, the diarrhea is improved, and in some cases the flushing is also reduced[7,8,70]. It remains to be seen whether its use will prevent the development of carcinoid heart disease[7,8].

In the case of insulinomas, long-acting somatostatin analogues are effective in 40-50% of cases[4,17,23,36,71,72]. However, their use in insulinoma patients requires careful monitoring, because they may not only inhibit the ectopic insulin secretion, but also the release of counter-regulatory hormones, such as growth hormone secretion and glucagon; which, in some patients, can worsen the hypoglycemia[4,10,23,72]. Fortunately, there are now an increasing number of other choices if diazoxide fails to control the hypoglycemia(Table 1)which include the mTor inhibitor, pasireotide, everolimus, beta blockers and in malignant insulinomas, PRRT(Table 1)[10,53,73–78].

Pasireotide, is a newer somatostatin receptor agonist, which has high affinity for 4 somatostatin-receptor subtypes(sst1,2,3,5), in contrast to octreotide/lanreotide which interact with high affinity with only sst2>sst5[8,78]. It is reported to be effective in F-NENs(Carcinoid syndrome, insulinomas, VIPomas, ACTHomas, GRFomas)in patients who fail treatment with Octreotide-LAR/Lanreotide-autogel[7,8,10,23,57,77–79].

PRRT has recently been approved for its antigrowth activity in patients with advanced NENs[4,80,81], and numerous recent small studies show it has beneficial potent effects in F-NENs which occurs independent of its antigrowth effects[10,53,67,73–75,80,81]. It has especially proven useful in patients failing somatostatin-analogue treatment with VIPomas, malignant insulinomas, Cushings syndrome, and Carcinoid syndrome[4,7,8,10,27,38,53,67,68,73–75,80–82]. In general PRRT treatment has been safe in these patients[80,83]although in up to 10% a hormonal crises may occur and thus additional prevent measures taken[8,84,85]. In Table 1 it is indicated, as a possible treatment in a number of F-NENs where it will likely also be effective but has not yet been reported in these patients. This approach appears highly effective and well tolerated and will likely increasingly become the most important secondary treatment in many of these syndromes.

5. Approach to NEN per se when pharmacological control effective

The only means to cure F-NENs is by surgical resection which is successful in 90-95% of insulinomas, 30-50% of ZES, <50% of other F-panNEN syndromes, and rarely in patients with Carcinoid syndrome[4,8,35,36,58]. Furthermore, with increased ability to control the hormone-excess state of F-NENs, increasingly the malignant natural history of the NEN per se is determining survival[4,86]. Therefore, all patients should undergo detailed tumor localization studies, with cross-sectional imaging(usually CT or MRI with contrast)and ⁶⁸ Ga-DOTATOC PET/CT to determine tumor location and extent, to determine the possibility of surgical excision or plan anti-tumor therapies[22,23,87–90]. In patients with insulinomas, gastrinomas or uncommonly, with small primary F-NET, additional tumor localization studies may be needed, either pre-surgically(endoscopic ultrasound, assessment of hormonal tumor gradients, etc)[3,87,89,91–95]or at the time of surgery(duodenotomy, intra-operatiave ultrasound, duodenal transillumination, etc)[11,49,50,89,96–99].

6. Expert Opinion

Recent studies demonstrate that the incidence of NENs is increasing in all countries with a 6.4-fold increase in the US from 1973 to 2012(6.9/100,000)[100]and within this group F-NENs are not uncommon, with up to 30% of panNEN patients having a F-panNEN and 3-13% of patients with a carcinoid having a F-NEN syndrome[7,10]. This means that clinicians are going to have increased exposure to these patients.

In the past the pharmacological armamentarium available to treat patients with F-NENs was very limited. In was not until the 1970’s the first effective drugs to treat F-NENs became available with diazoxide for insulinomas in 1973, and cimetidine(1977), ranitidine(1981),and famotidine(1985)for ZES[44,46,101,102]. In the 1980s the first PPI, omeprazole(1988)became available for the treatment of ZES and octreotide for the treatment of hormone-excess states(acromegaly, VIPomas). Whereas the availability of omeprazole and other PPIs largely solved the problem of the control of acid hypersecretion seen in ZES resulting in a dramatic decrease in mortality in these patients due to uncontrolled acid hypersecretion[26,41,47], this was not the case with a number of the other F-NEN syndromes. While the availability of the long acting somatostatin analogues(Octreotide-LAR,Lanreotide-autogel), in most cases initially at least partially controlled the hormone-excess in these other non-ZES,F-NEN syndromes(except insulinomas), with time resistance developed, and it became increasingly difficult to control the hormone-excess state symptoms[8,10]. More recently(since 2010)a number of new pharmacologic agents(telotristat,pasireotide,cinacalcet)as well as PRRT(2018) have become available which have proven effective in a number of these syndromes, in patients refractory to the initial treatment agent used(see Table 1, somatostatin analogues in most cases)[10,23,57,70,74–76,84,103,103–105]. The availability of these new treatment approaches combined with the increased use of surgical resection, and liver -directed therapies, has resulted in the increased ability to control symptoms long-term due to the hormone-excess state in most patients[10,23,36,84,106,107].

Although the availability of these multiple therapeutic approaches has increased the ability to control these hormone-excess states in patients with F-NENS, there still remain a number of treatment issues and a number of controverses. These include the best order of the secondary treatment regimens where multiple options are available, the long-term effectiveness of most of these secondary treatments, clear algorithms for diagnosis of the disorders when any treatment regimen is already started before the diagnosis is established, and the effectiveness of PRRT in the initial and long-term control of most F-NENs. The recent reporting of the effectiveness of PRRT in malignant insulinomas, refractory carcinoid syndrome, Cushings syndrome, and VIPomas as well as a few other F-NENs[4,7,10,34,74,75]is particularly promising, in that it is well tolerated, safe, effective, and independent of anti-growth effects[8,73,80,83,108]and thus may play and increasing role in the treatment of the hormone-excess state.

In this short article a number of issues are briefly reviewed and discussed.